June COVID-19 update: Reassuring data on spironolactone and ACE2 risks

Disclaimer: I am not a medical professional and this is not medical advice. Our understanding of the pandemic is evolving rapidly; this information may be superseded by later and more conclusive findings. This article was last updated on June 30, 2020.

At the end of March, I addressed claims circulating in style and beauty publications about the medication spironolactone and its alleged connection to COVID-19 risk. Spironolactone works to block and suppress the action of testosterone and is sometimes prescribed for the hormonal treatment of acne in cis women, as well as being used to diminish the action of testosterone in trans women who still have testes. The concerns put forth by dermatologist Dr. Ellen Marmur and a handful of others posited that because spironolactone can increase the expression of the ACE2 receptor by cells of the human body, and the SARS-CoV-2 virus which causes COVID-19 must make use of this ACE2 receptor to enter and infect cells, taking spironolactone could therefore place one at greater risk of contracting COVID-19 or suffering a more severe course of the disease. For these reasons, Marmur had recommended to her patients that they discontinue spironolactone and use other medications for the treatment of acne.

Following these claims, numerous medical professionals stated in several publications that any actual connection between increased ACE2 expression and increased risk of SARS-CoV-2 infection or severe disease has not been established, and so there is not sufficient evidence to say that medications which increase ACE2 expression should be avoided (Sanchis-Gomar et al., 2020; Patel & Verma, 2020; Vaduganathan et al., 2020). In fact, the available evidence was so limited and ambiguous that the possibility could not be ruled out that increased ACE2 expression might even be protective against SARS-CoV-2 infection, and so medications with this effect could potentially be beneficial in treating COVID-19.

Additionally, the original and still commonplace use of spironolactone was not as an antiandrogen, but as a diuretic used in the treatment of high blood pressure and heart failure. Even as the possibility was raised that other heart medications which also have the potential to boost ACE2 expression, such as angiotensin II receptor blockers (ARBs) and ACE inhibitors (ACEis; ACE and ACE2 are two distinct receptors), could increase risk of COVID-19 susceptibility or severe disease, these medications are also crucial for the management of serious chronic conditions. For that reason, organizations including the American Heart Association, Heart Failure Society of America, American College of Cardiology, European Society of Cardiology, and European Medicines Agency all stated in mid-March that patients taking these medications should continue taking them, and any risk of infection or more severe COVID-19 disease was not established sufficiently as to warrant discontinuing these medications in order to attempt to reduce COVID-19 risk.

Three months later, we now have actual patient data on the relation between these medications and COVID-19 disease, not just theory. Although studies of COVID-19 patients have not focused on spironolactone specifically, they do cover the ARB and ACEi drugs which were the subject of similar concerns about the possibility of increasing ACE2 expression and therefore increasing COVID-19 susceptibility or severity. These studies now show that in practice there appears to be no such risk associated with these medications.

• Reynolds et al. (2020) examined the medical histories of 12,594 people with electronic health records in the NYU Langone Health system who had been tested for COVID-19. Patients who had been taking ARBs or ACE inhibitors were not any more likely to receive a positive test result or suffer a more severe course of COVID-19 than those who were not taking these medications.
• Mancia et al. (2020) studied 6,272 COVID-19 patients from the Lombardy region of Italy, finding that patients more commonly used ARBs and ACEis than matched controls “because of their higher prevalence of cardiovascular disease” – as the authors note, “all other major antihypertensive drugs, such as calcium-channel blockers, beta-blockers, and diuretics, were also used more frequently in patients with Covid-19”. Use of ARBs and ACEis in COVID-19 patients was not found to be associated with a severe or fatal course of the disease.
• de Abajo et al. (2020) examined the histories of 1,139 confirmed cases of COVID-19 in Madrid, and found that use of ARBs and ACEis was not associated with an increased likelihood of COVID-19 requiring admission to a hospital, increased likelihood of admission to an intensive care unit, or increased likelihood of death. ARBs and ACEis were also not found to be associated with a greater likelihood of any of these outcomes than use of other classes of antihypertensive drugs. The authors conclude that “the data available, along with the important role of ACE inhibitors and angiotensin-receptor blockers in the management of several cardiovascular diseases, do not support their discontinuation as a preventive measure against COVID-19.”
• Fosbøl et al. (2020) studied 4,480 COVID-19 patients in Denmark, finding that ARBs and ACEis were not associated with a greater risk of severe disease or death, and that “ACEI/ARB use compared with other antihypertensive drugs was not significantly associated with higher incidence of COVID-19”. The authors conclude that their results “do not support discontinuation of ACEI/ARB medications that are clinically indicated in the context of the COVID-19 pandemic.”

Additionally, in a meta-analysis of 15 studies including 7,410 COVID-19 patients, Pranata et al. (2020) found that “the use of ACEI/ARB was associated with neither increased nor decreased mortality rate in hypertensive COVID-19 patients”, and “there was no statistically significant association between the use of ACEI/ARB in hypertensive patients and severe COVID-19.” The results of these studies collectively show that a potential increase in ACE2 receptor expression, the mechanism by which taking spironolactone was hypothesized to create a greater risk of COVID-19 infection and greater disease severity, does not appear to be associated with these negative outcomes. While research into the many aspects of COVID-19 is ongoing, these studies have not found evidence that would support the presence of such a danger posed by taking spironolactone. ■